No abstract

Augmenting antitumor immunity is a promising way to enhance the potency of oncolytic adenoviral therapy. Granulocyte-macrophage colony-stimulating factor (GMCSF) can mediate antitumor effects by recruiting natural killer cells and by induction of tumor-specific CD8(+) cytotoxic T-lymphocytes. Serotype 5 adenoviruses (Ad5) are commonly used in cancer gene therapy. However, expression of the coxsackie-adenovirus receptor is variable in many advanced tumors and preclinical data have demonstrated an advantage for replacing the Ad5 knob with the Ad3 knob. Here, a 5/3 capsid chimeric and p16-Rb pathway selective oncolytic adenovirus coding for GMCSF was engineered and tested preclinically. A total of 21 patients with advanced solid tumors refractory to standard therapies were then treated intratumorally and intravenously with Ad5/3-D24-GMCSF, which was combined with low-dose metronomic cyclophosphamide to reduce regulatory T cells. No severe adverse events occurred. Analysis of pretreatment samples of malignant pleural effusion and ascites confirmed the efficacy of Ad5/3-D24-GMCSF in transduction and cell killing. Evidence of biological activity of the virus was seen in 13/21 patients and 8/12 showed objective clinical benefit as evaluated by radiology with Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Antiadenoviral and antitumoral immune responses were elicited after treatment. Thus, Ad5/3-D24-GMCSF seems safe in treating cancer patients and promising signs of efficacy were seen.

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimer's disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinson's disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.

This quantitative MRI study provides support for a possible association between structural and biochemical substrates and severe drug-resistant major depression.